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Pancreatic beta cells are resistant to RIPK1 kinase-mediated death

par Takiishi, Tatiana ;Xiao, Peng ;Gurzov, Esteban Nicolas ;Bertrand, Mathieu;Cardozo, Alessandra K
Référence (2022-09-19: Stockholm, Sweden), European Association for the Study of Diabetes, 58th, Diabetologia (vol. 65, p. 211)
Publication Publié, 2022-09-19

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Résumé :

Background and aims: Type 1 diabetes (T1D) is caused by progressive immune-mediated loss of insulin-producing β-cells. Inflammation is very detrimental to β-cell function and survival, moreover, both apoptosis and necrosis have been implicated as a mechanism of β-cell loss in T1D. The protein receptor interacting serine/threonine kinase 1 (RIPK1) promotes inflammation either directly by serving as a scaffold for NF-κB and MAPK activation, or instead indirectly by acting as a kinase that triggers the dismantlement of the cell by apoptosis or necroptosis. To investigate if RIPK1 kinase activity is involved in T1D pathology, we evaluated whether RIPK1 kinase is activated in β-cells and whether this activation would affect cell survival. Furthermore, we investigated if mice lacking RIPK1 kinase activity would present glucose abnormalities in homeostasis or different susceptibility to immune-mediated diabetes in the multiple low-dose streptozotocin (MLDSTZ) model.Materials and methods: The RIPK1 knockin mouse line carrying a mutation mimicking serine 25 phosphorylation (Ripk1S25D/S25D), which abrogates RIPK1 kinase activity, was utilized to assess the in vivo role of RIPK1 in β-cells both in physiological conditions and after MLDSTZ induced diabetes. Weekly glycemia and bodyweight of Ripk1S25D/S25D mice and wild type littermates (Ripk1+/+) were followed. IpGTT, iTT and pancreas insulin content measurements were performed. In vitro, β- cell death and RIPK1ser166 phosphorylation (a marker of activation) was analysed in mouse islets and EndoC-βH1 cells exposed to conditions known to induce RIPK1-dependent apoptosis/necroptosis: TNF + BV6 (a cIAP inhibitor), with or without zVAD.fmk (pan caspase inhibitor) or Nec-1 (RIPK1 kinase inhibitor).Results: Under physiological conditions Ripk1S25D/S25D mice did not display any overt abnormalities and showed normal weight gain, glyce- mia and body mass composition, presenting normal glucose metabolism and β-cell function when compared to control littermates. Moreover, disease progression was not different between Ripk1S25D/S25D and Ripk1+/+ mice when rendered diabetic by MLDSTZ. Both Ripk1S25D/ S25D and Ripk1+/+ displayed hyperglycaemia, glucose intolerance and significant loss of pancreatic insulin content, without any significant alter- ations caused by absence of RIPK1 kinase function. In vitro, RIPK1 enzymatic activity was highly induced by TNF+BV6+zVAD both in mouse islets and human β-cells. However, RIPK1 activation did not lead to β-cell death.Conclusion: RIPK1 kinase does not affect glucose homeostasis nor diabetes presentation in mice. Contrary to what is described on most cell types, pancreatic β-cells are resistant to RIPK1-dependent cell death. This may reflect an adaptation to the inability of β-cells to proliferate and self-renewal.Supported by: FNRS-EOS; CDR J.0109.22 Disclosure: T. Takiishi: Grants; FNRS-EOS.